Malaria chemotherapy has suffered from development of resistance against drugs introduced to the field. Current Artemisinin Combination Therapies (ACTs) were introduced to limit drug resistance, but strains that respond slowly to artemisinin have now arisen in Southeast Asia, threatening to displace the best current therapy against this widespread scourge. As a result, there have been urgent calls for development of novel antimalarial drugs that act against different targets than ACTs. One promising target for drug development is the uptake of glucose via the Plasmodium falciparum hexose transporter, PfHT. Malaria parasites live inside red blood cells in the stages that cause disease, have abundant glucose available in the blood, and metabolize large amounts of glucose inefficiently by glycolysis. Hence, these parasites are critically dependent on uptake of glucose through PfHT for survival. PfHT has been validated as a drug target by both genetic and chemical methods. Thus the PfHT gene cannot be knocked out, and glucose analogs that selectively inhibit the transport function of PfHT, versus the highly sequence- divergent human glucose transporters, are lethal to the parasite both in vitro and in a mouse model of malaria. However, the current challenge is to identify drug-like compounds that selectively inhibit PfHT that can serve as leads for development of new drugs. In preliminary work, we have screened several focused libraries of compounds with demonstrated antimalarial activity in vitro and discovered several hits that selectively inhibit PfHT versus human GLUT1. This proposal will further advance these compounds, and analogs thereof, toward development of orally bioavailable drugs that target PfHT. In addition, a different library of Malaria Actives that potenly inhibit malaria growth will be screened for other selective inhibitors of PfHT. These Malaria Actives represent a small focused library of compounds with ideal properties as inhibitors of malaria growth and were distilled from a phenotypic screen of 1.25 million compounds, thus widening considerably the initial chemical space interrogated. These multiple screens have the potential to deliver diverse chemical scaffolds that potently inhibit PfHT and parasite growth and can serve as novel leads for drug development. The major objective of this exploratory R21 proposal is to identify multiple chemical scaffolds that can be exploited subsequently for development of new antimalarial drugs via their ability to inhibit uptake of glucose, a critical nutrient for the malaria parasite.